The prefrontal cortex (PFC) has been called "the organ of civilization" (Luria). The most anterior part of cerebral cortex, the PFC consists of multiple areas that mediate a wide range of higher-order behaviors in mammals. Despite years of intensive neuroanatomical and functional studies, little is known about the genetic mechanisms that pattern this structure during development. It has been recognized that fibroblast growth factor (FGF) signaling from the rostral patterning center could have a central role in regulating rostral telencephalic development. A subset of FGF genes are expressed in the rostral patterning center in the embryonic telencephalon. Recent evidence shows that FGFs regulate the graded expression of regulatory genes (i.e. Emx2) in the cortical neuroepithelium, which may specify the initial distribution of PFC regional subdivisions and ultimately mature areas. I have devised a novel panel of gene expression markers to study the roles of Fgf17 and Fgf8, and genetic interactions between Fgf17 and Emx2 in patterning the frontal cortex. In addition, I have identified signaling mechanisms and genetic interactions during early forebrain development that may contribute to the postnatal regionalization phenotypes. Finally, I have initiated behavioral studies through collaborations with other laboratories to investigate higher-order behaviors that are dependent on intact PFC function. I have found that Fgf17, Fgf8 and Emx2 each play unique roles in the early regionalization of the PFC, and that Fgf17 and Emx2 specifically interact on the genetic level to regulate this process. In addition, Fgf17 mutant mice exhibit circumscribed deficits in social behavior and associated selective hypo-activation of the dorsal PFC. These studies reveal that the organization of subdivisions within a higher-order cortical area is partially under genetic control, and suggest that mispatterning of the PFC via genetic mutation may contribute to abnormal behavior.

Synaptogenesis has been extensively studied along with dendrite spine development in glutamatergic pyramidal neurons, however synapse development in cortical interneurons, which are largely aspiny, is comparatively less well understood. Dact1, one of 3 paralogous Dact (Dapper/Frodo) proteins in mammals, is a scaffold protein implicated in both the Wnt/β-catenin and the Wnt/Planar Cell Polarity pathways. We show here that Dact1 is expressed in migratory immature cortical interneurons. Although Dact1 is expressed in developing cortical interneurons, constitutive Dact1 mutant mice have no major defects in either the migration or numbers of these neurons. These mice do have defects in the elaboration of cortical interneuron dendrite morphology and synapse numbers along their primary dendrites. Using a conditional knock out strategy, we selectively eliminated Dact1 from cortical interneurons using a Dlx-I12b enhancer-Cre (I12bCre) allele, and thereby demonstrate a cell-autonomous role for Dact1 in postsynaptic development. Additionally, we show that synapse numbers in Dact1 deficient interneurons can be rescued by interneuron-specific expression of Dact1 itself, its binding partner Dishevelled-1, or Disrupted in Schizophrenia-1 (DISC1), a gene implicated in schizophrenia. In sum, our results support a novel cell-autonomous postsynaptic role for Dact1, in cooperation with Dishevelled-1 and DISC1, in the formation and maintenance of synapses on cortical interneuron dendrites.

Background: Linkage studies in autism have identified susceptibility loci on chromosomes 2q and 7q, regions containing the DLX1/2 and DLX5/6 bigene clusters. The DLX genes encode homeodomain transcription factors that control craniofacial patterning and differentiation and survival of forebrain inhibitory neurons. We investigated the role that sequence variants in DLX genes play in autism by in-depth resequencing of these genes in 161 autism probands from the AGRE collection. Results: Sequencing of exons, exon/ intron boundaries and known enhancers of DLX1, 2, 5 and 6 identified several nonsynonymous variants in DLX2 and DLX5 and a variant in a DLX5/6intragenic enhancer. The nonsynonymous variants were detected in 4 of 95 families from which samples were sequenced. Two of these four SNPs were not observed in 378 undiagnosed samples from North American populations, while the remaining 2 were seen in one sample each. Conclusion: Segregation of these variants in pedigrees did not generally support a contribution to autism susceptibility by these genes, although functional analyses may provide insight into the biological understanding of these important proteins.

Embryonic medial ganglionic eminence (MGE) cells transplanted into the adult brain can disperse, migrate, and differentiate to neurons expressing GABA, the primary inhibitory neurotransmitter. It has been hypothesized that grafted MGE precursors could have important therapeutic applications increasing local inhibition, but there is no evidence that MGE cells can modify neural circuits when grafted into the postnatal brain. Here we demonstrate that MGE cells grafted into one location of the neonatal rodent brain migrate widely into cortex. Grafted MGE-derived cells differentiate into mature cortical interneurons; the majority of these new interneurons express GABA. Based on their morphology and expression of somatostatin, neuropeptide Y, parvalbumin, or calretinin, we infer that graft-derived cells integrate into local circuits and function as GABA-producing inhibitory cells. Whole-cell current-clamp recordings obtained from MGE-derived cells indicate firing properties typical of mature interneurons. Moreover, patch-clamp recordings of IPSCs on pyramidal neurons in the host brain, 30 and 60 d after transplantation, indicated a significant increase in GABA-mediated synaptic inhibition in regions containing transplanted MGE cells. In contrast, synaptic excitation is not altered in the host brain. Grafted MGE cells, therefore, can be used to modify neural circuits and selectively increase local inhibition. These findings could have important implications for reparative cell therapies for brain disorders.